EP1030667A1 - Verwendung von mirtazapine zur behandlung von schlafapnoen - Google Patents
Verwendung von mirtazapine zur behandlung von schlafapnoenInfo
- Publication number
- EP1030667A1 EP1030667A1 EP98962348A EP98962348A EP1030667A1 EP 1030667 A1 EP1030667 A1 EP 1030667A1 EP 98962348 A EP98962348 A EP 98962348A EP 98962348 A EP98962348 A EP 98962348A EP 1030667 A1 EP1030667 A1 EP 1030667A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- mirtazapine
- sleep
- apneas
- sleep apneas
- ssri
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 201000002859 sleep apnea Diseases 0.000 title claims abstract description 23
- RONZAEMNMFQXRA-UHFFFAOYSA-N mirtazapine Chemical compound C1C2=CC=CN=C2N2CCN(C)CC2C2=CC=CC=C21 RONZAEMNMFQXRA-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 229960001785 mirtazapine Drugs 0.000 title claims abstract description 16
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 claims abstract description 11
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 241001465754 Metazoa Species 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 abstract description 16
- 229960002464 fluoxetine Drugs 0.000 abstract description 4
- RTHCYVBBDHJXIQ-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine Chemical compound C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-UHFFFAOYSA-N 0.000 abstract 1
- 230000007958 sleep Effects 0.000 description 10
- 208000008784 apnea Diseases 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 8
- 230000037396 body weight Effects 0.000 description 6
- 230000029058 respiratory gaseous exchange Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 230000000414 obstructive effect Effects 0.000 description 4
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 3
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 2
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 2
- 208000003417 Central Sleep Apnea Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 229960001653 citalopram Drugs 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- 229960004038 fluvoxamine Drugs 0.000 description 2
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 208000001797 obstructive sleep apnea Diseases 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229960002296 paroxetine Drugs 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- 230000000862 serotonergic effect Effects 0.000 description 2
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 2
- 229960002073 sertraline Drugs 0.000 description 2
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 1
- WYWNEDARFVJQSG-UHFFFAOYSA-N 2-methylserotonin Chemical compound C1=C(O)C=C2C(CCN)=C(C)NC2=C1 WYWNEDARFVJQSG-UHFFFAOYSA-N 0.000 description 1
- FWYRGHMKHZXXQX-UHFFFAOYSA-N 3-(3,4-dichlorophenyl)-2-(dimethylamino)-2-methylpropan-1-ol Chemical compound CN(C)C(C)(CO)CC1=CC=C(Cl)C(Cl)=C1 FWYRGHMKHZXXQX-UHFFFAOYSA-N 0.000 description 1
- QISOBCMNUJQOJU-UHFFFAOYSA-N 4-bromo-1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1NN=CC=1Br QISOBCMNUJQOJU-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 208000007590 Disorders of Excessive Somnolence Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Natural products OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- FELGMEQIXOGIFQ-UHFFFAOYSA-N Ondansetron Chemical compound CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 229920002472 Starch Chemical class 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- -1 acid addition salts Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 230000037007 arousal Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000001913 cellulose Chemical class 0.000 description 1
- 229920002678 cellulose Chemical class 0.000 description 1
- 229950000303 cericlamine Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 208000020020 complex sleep apnea Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- FSIRGTNPQFDCCD-QGMBQPNBSA-N cyanodothiepin Chemical compound C1SC2=CC=C(C#N)C=C2C(=C/CCN(C)C)/C2=CC=CC=C21 FSIRGTNPQFDCCD-QGMBQPNBSA-N 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- OJSFTALXCYKKFQ-YLJYHZDGSA-N femoxetine Chemical compound C1=CC(OC)=CC=C1OC[C@@H]1[C@@H](C=2C=CC=CC=2)CCN(C)C1 OJSFTALXCYKKFQ-YLJYHZDGSA-N 0.000 description 1
- 229950003930 femoxetine Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 208000018875 hypoxemia Diseases 0.000 description 1
- 229950006314 ifoxetine Drugs 0.000 description 1
- ZHFIAFNZGWCLHU-YPMHNXCESA-N ifoxetine Chemical compound CC1=CC=CC(O[C@@H]2[C@@H](CNCC2)O)=C1C ZHFIAFNZGWCLHU-YPMHNXCESA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- MJJDYOLPMGIWND-UHFFFAOYSA-N litoxetine Chemical compound C=1C=C2C=CC=CC2=CC=1COC1CCNCC1 MJJDYOLPMGIWND-UHFFFAOYSA-N 0.000 description 1
- 229950004138 litoxetine Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 201000006646 mixed sleep apnea Diseases 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000008035 nerve activity Effects 0.000 description 1
- 229960005343 ondansetron Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 210000003105 phrenic nerve Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 229940095055 progestogen systemic hormonal contraceptives Drugs 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 239000003169 respiratory stimulant agent Substances 0.000 description 1
- 229940066293 respiratory stimulants Drugs 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000002400 serotonin 2A antagonist Substances 0.000 description 1
- 239000002484 serotonin 2C antagonist Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000008107 starch Chemical class 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 229960002791 zimeldine Drugs 0.000 description 1
- OYPPVKRFBIWMSX-SXGWCWSVSA-N zimeldine Chemical compound C=1C=CN=CC=1C(=C/CN(C)C)\C1=CC=C(Br)C=C1 OYPPVKRFBIWMSX-SXGWCWSVSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/16—Central respiratory analeptics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention pertains to the treatment of sleep apneas.
- Sleep apnea is defined as the cessation of breathing during sleep. It comprises a spectrum of respiration- related disorders with varying severity and morbidity, involving periods, during sleep, in which airflow is disturbed.
- the usual classification of sleep apneas distinguishes obstructive, central, and mixed apneas, depending on the presence or absence of respiratory efforts during the periods in which airflow has ceased.
- obstructive sleep apnea syndrome which is the most familiar apnea, sporadic recurring collapse of the patient's upper airway occurs during sleep.
- the sleep apnea syndrome today is regarded as a serious problem, as it occurs widely, and there is a true lack of an effective treatment.
- Surgical and mechanical interventions have been suggested and tried as treatments, as has oxygen administration during sleep, but none of these are recognised to be very suitable.
- Pharmacological intervention has also been tried, but with little success.
- several kinds of respiratory stimulants, theophylline, antidepressants, and progestogens have been used to treat sleep apneas, but none of these has been found to be very effective. It is an object of the present invention to provide an effective medicine against sleep apneas.
- the invention is a method for the treatment of an animal, for example, a mammal including a human patient, suffering from sleep apnea, comprising administering an effective amount of mirtazapine.
- the invention also involves the use of mirtazapine for the manufacture of a medicament for the treatment of sleep apnea.
- the applicant with the hindsight of the unexpected effect of the invention, believes that it is the particular serotonergic profile of mirtazapine which is responsible for the efficacy against sleep apnea.
- the invention resides in the finding that an effective medicine against sleep apneas is provided on the basis of the compound mirtazapine.
- This compound displays a combined serotonergic antagonistic activity to the effect that it simultaneously is a combined 5HT2A, 5HT2C and 5HT3 antagonist.
- the invention in general pertains to the use of this compound for manufacturing a medicament for treating sleep apneas, Surpisingly, the compound is not only useful as a therapy against sleep apneas of the central type, but also against sleep apneas of the obstructive and mixed types.
- Mirtazapine is known, e.g. from US 4,062,848.
- the present invention includes the use of any particular enantiomer alone, or in a mixture with one or more steroiseomers, in any proportion including racemic mixtures.
- the present invention includes any salts of the compound, such as acid addition salts, for example, hydrochloric, fumaric, maleic, citric or succinic acid, these acids being mentioned only by way of illustration and without implied limitation. These compounds can be prepared in accordance with US 4,062,848, incorporated herein by reference.
- SSRI selective serotonin reuptake inhibitor
- SSRI's and pharmaceutically acceptable salts thereof, are known and have been available since the early 1980s. They include zimelidine, fluoxetine and fluvoxamine. Other SSRI's are for example citalopram, cericlamine, femoxetine, ifoxetine, cyanodothiepin, sertraline, paroxetine, and litoxetine.
- SSRI's are known to the skilled person, and may be prepared by any method known in the art.
- fluoxetine or pharmaceutically acceptable salts thereof can be prepared in accordance with US 4,314,081, incorporated herein by reference.
- mirtazapine also has antidepressant and anxiolytic properties, which helps to overcome secondary symptoms of which sleep apnea patients may suffer. Moreover mirtazapine improves the quality of sleep in general, which up to date has not been achieved with treatments of sleep apnea.
- the compounds used according to the invention are to be administered in dosages of from 0,01 to 30 mg per kilogram body weight of the recipient per day, preferably in the range of 0,1 to 5 mg per kg body weight. In most instances, the preferred dosage of mirtazapine is 5 to 45 mg per day, and more preferably 15-30 mg.
- the SSRI dose may vary depending on the potency and efficacy of the specific active substance, but will generally be in the range of from 5 to 300 mg per day. E.g. citalopram and paroxetine will have a suitable dose of 40-50 mg, while the doses for fluvoxamine and sertraline will be 200-300 mg per day.
- a suitable dose of an SSRI or a pharmaceutically acceptable salt thereof for administration to a human will be in the range of 0.01 to 50 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 3 mg per kilogram body weight per day.
- the preferred SSRI is fluoxetine which, administered in a dose within the range of 0.01 to 10 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 1 mg per kilogram body weight per day, together with the above preferred dose of mirtazapine forms the best choice for providing a highly effective medicament for the treatment of sleep apneas of the obstructive and mixed types.
- the method of treatment of sleep apneas wherein the compounds according to the invention are administered for therapy to an animal e.g. a mammal including a human may be carried out in conventional manner, using all kinds of methods, including parenteral, peroral or rectal administration. Administration in the form or oral dosage units, such as tablets or capsules, is preferred.
- the compound can be mixed with all kinds of pharmaceutically acceptable carriers, depending on the method of administration intended.
- the active compound is taken up in known manner in a composition from which granules or tablets are prepared.
- dosage unit generally refers to physically discrete units suitable as unitary dosages for humans, each containing a predetermined quantity of active material calculated to produce the desired effect, for instance tablets, pills, powders, suppositories, capsules and the like.
- compositions for making such dosage units are well-known to those skilled in the art. For example, conventional techniques for making tablets and pills, containing active ingredients, are described in the standard reference, Gennaro et al., Remington's Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture).
- dosage units e.g. tablets
- conventional additives e.g. fillers, colorants, polymeric binders and the like is contemplated.
- any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used in the one or more of the compositions.
- Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like used in suitable amounts. Lactose is a preferred carrier. Mixtures of carriers can also be used.
- the manufacture of the dosage units according to the invention can involve standard pharmaceutical methods known to the skilled person without further elucidation.
- the efficacy of the compounds according to the invention is tested by studying the effects of administration of mirtazapine (in the range of from 0.05 to 25 mg/kg) in adult Sprague-Dawley rats by monitoring sleep, respiration and blood pressure for a minimum of 6 hours. This follows an accepted physiological animal model (ref. Monti et al., Pharmacol.Biochem.Behav., 51:125-131;1995). The effective suppression by mirtazapine of sleep apneas in the rat model is indicative for similar efficacy in humans.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK98962348T DK1030667T3 (da) | 1997-11-14 | 1998-11-13 | Anvendelse af mirtazapin til fremstilling af et lægemiddel til behandling af sövnapnö |
| EP98962348A EP1030667B1 (de) | 1997-11-14 | 1998-11-13 | Verwendung von mirtazapine zur herstellung eines medikaments zur behandlung von schlafapnoen |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP97203548 | 1997-11-14 | ||
| EP97203548 | 1997-11-14 | ||
| PCT/EP1998/007330 WO1999025356A1 (en) | 1997-11-14 | 1998-11-13 | Use of mirtazapine for treating sleep apneas |
| EP98962348A EP1030667B1 (de) | 1997-11-14 | 1998-11-13 | Verwendung von mirtazapine zur herstellung eines medikaments zur behandlung von schlafapnoen |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP1030667A1 true EP1030667A1 (de) | 2000-08-30 |
| EP1030667B1 EP1030667B1 (de) | 2005-03-02 |
Family
ID=8228923
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP98962348A Expired - Lifetime EP1030667B1 (de) | 1997-11-14 | 1998-11-13 | Verwendung von mirtazapine zur herstellung eines medikaments zur behandlung von schlafapnoen |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US6303595B1 (de) |
| EP (1) | EP1030667B1 (de) |
| JP (1) | JP2001522891A (de) |
| KR (1) | KR20010032009A (de) |
| CN (1) | CN1154495C (de) |
| AT (1) | ATE289816T1 (de) |
| AU (1) | AU737590B2 (de) |
| BR (1) | BR9815098A (de) |
| CA (1) | CA2309744A1 (de) |
| CZ (1) | CZ296282B6 (de) |
| DE (1) | DE69829202T2 (de) |
| DK (1) | DK1030667T3 (de) |
| ES (1) | ES2238781T3 (de) |
| HK (1) | HK1029932A1 (de) |
| HU (1) | HUP0100080A3 (de) |
| IL (2) | IL135825A0 (de) |
| NO (1) | NO20002218L (de) |
| PL (1) | PL192272B1 (de) |
| PT (1) | PT1030667E (de) |
| TR (1) | TR200001293T2 (de) |
| WO (1) | WO1999025356A1 (de) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10603272B2 (en) | 2015-02-27 | 2020-03-31 | Kindred Biosciences, Inc. | Stimulation of appetite and treatment of anorexia in dogs and cats |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060241164A1 (en) * | 1998-02-27 | 2006-10-26 | The Board Of Trustees Of The University Of Illinoi | Pharmacological treatment for sleep apnea |
| CA2321900C (en) | 1998-02-27 | 2011-07-19 | The Board Of Trustees Of The University Of Illinois | Agents with serotonin-related activity for the treatment for sleep apnea |
| US7160898B2 (en) * | 2001-12-14 | 2007-01-09 | Board Of Trustees Of The University Of Illinois | Pharmacological treatment for sleep apnea |
| CA2396209C (en) * | 2000-02-11 | 2009-09-01 | Akzo Nobel N.V. | The use of mirtazapine for the treatment of sleep disorders |
| US20020183306A1 (en) * | 2001-05-30 | 2002-12-05 | Pfizer Inc. | Combination treatment for sleep disorders including sleep apnea |
| UA83666C2 (ru) | 2003-07-10 | 2008-08-11 | Н.В. Органон | Способ получения энантиомерно чистого миртазапина |
| US7838029B1 (en) | 2003-07-31 | 2010-11-23 | Watson Laboratories, Inc. | Mirtazapine solid dosage forms |
| WO2005023767A2 (en) | 2003-09-10 | 2005-03-17 | Brentwood Equities Ltd. | Diastereomers of 4-aryloxy-3-hydroxypiperidines |
| WO2006023702A2 (en) * | 2004-08-20 | 2006-03-02 | Cypress Bioscience, Inc. | Method for treating sleep related breathing disorders with setiptiline |
| WO2006055854A2 (en) * | 2004-11-17 | 2006-05-26 | Cypress Bioscience, Inc. | Methods for reducing the side effects associated with mirtazapine treatment |
| US8512751B2 (en) | 2004-12-20 | 2013-08-20 | Collegium Pharmaceutical, Inc. | Pharmaceutical compositions for sleep disorders |
| JP5635905B2 (ja) | 2007-04-11 | 2014-12-03 | メルク・シャープ・エンド・ドーム・ベー・フェー | ミルタザピンの調製方法 |
| WO2008157094A1 (en) * | 2007-06-13 | 2008-12-24 | Cypress Bioscience, Inc. | Improving the tolerability of mirtazapine and a second active by using them in combination |
| WO2013188806A1 (en) * | 2012-06-14 | 2013-12-19 | The Regents Of The University Of Michigan | Sleep apnea treatment |
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| US4314081A (en) * | 1974-01-10 | 1982-02-02 | Eli Lilly And Company | Arloxyphenylpropylamines |
| EP0517984A1 (de) | 1991-06-11 | 1992-12-16 | Merrell Dow Pharmaceuticals Inc. | Amidanaloge-Derivate von methanoverbrückten Chinolizinen |
| EP0866711B1 (de) * | 1995-10-24 | 2006-07-26 | Grünenthal GmbH | Montirelin zur verhinderung der schlafapnoe |
| SE9504537D0 (sv) * | 1995-12-19 | 1995-12-19 | Jan Hedner | Sätt att behandla och diagnosticera andningsstörningar under sömn och medel för utförande av sättet |
| IL121076A (en) * | 1996-06-19 | 2000-10-31 | Akzo Nobel Nv | Pharmaceutical combinations comprising mirtazapine and one or more selective serotonin reuptake inhibitors |
| US6117855A (en) * | 1996-10-07 | 2000-09-12 | Merck Sharp & Dohme Ltd. | Use of a NK-1 receptor antagonist and an antidepressant and/or an anti-anxiety agent |
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1998
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- 1998-11-13 JP JP2000520789A patent/JP2001522891A/ja active Pending
- 1998-11-13 EP EP98962348A patent/EP1030667B1/de not_active Expired - Lifetime
- 1998-11-13 TR TR2000/01293T patent/TR200001293T2/xx unknown
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- 1998-11-13 IL IL13582598A patent/IL135825A0/xx active IP Right Grant
- 1998-11-13 HU HU0100080A patent/HUP0100080A3/hu unknown
- 1998-11-13 ES ES98962348T patent/ES2238781T3/es not_active Expired - Lifetime
- 1998-11-13 CA CA002309744A patent/CA2309744A1/en not_active Abandoned
- 1998-11-13 CN CNB988111349A patent/CN1154495C/zh not_active Expired - Fee Related
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- 1998-11-13 KR KR1020007005121A patent/KR20010032009A/ko not_active Application Discontinuation
- 1998-11-13 AU AU17548/99A patent/AU737590B2/en not_active Ceased
- 1998-11-13 DK DK98962348T patent/DK1030667T3/da active
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- 1998-11-13 AT AT98962348T patent/ATE289816T1/de not_active IP Right Cessation
- 1998-11-13 WO PCT/EP1998/007330 patent/WO1999025356A1/en not_active Application Discontinuation
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2000
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- 2000-04-28 NO NO20002218A patent/NO20002218L/no not_active Application Discontinuation
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2001
- 2001-02-05 HK HK01100800A patent/HK1029932A1/xx not_active IP Right Cessation
Non-Patent Citations (1)
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| See references of WO9925356A1 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10603272B2 (en) | 2015-02-27 | 2020-03-31 | Kindred Biosciences, Inc. | Stimulation of appetite and treatment of anorexia in dogs and cats |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1278731A (zh) | 2001-01-03 |
| CN1154495C (zh) | 2004-06-23 |
| KR20010032009A (ko) | 2001-04-16 |
| PL192272B1 (pl) | 2006-09-29 |
| DE69829202D1 (de) | 2005-04-07 |
| CZ20001751A3 (cs) | 2000-10-11 |
| HUP0100080A2 (hu) | 2001-08-28 |
| AU737590B2 (en) | 2001-08-23 |
| ATE289816T1 (de) | 2005-03-15 |
| IL135825A (en) | 2006-12-31 |
| CA2309744A1 (en) | 1999-05-27 |
| CZ296282B6 (cs) | 2006-02-15 |
| HUP0100080A3 (en) | 2002-05-28 |
| DK1030667T3 (da) | 2005-06-20 |
| ES2238781T3 (es) | 2005-09-01 |
| EP1030667B1 (de) | 2005-03-02 |
| TR200001293T2 (tr) | 2002-09-23 |
| PT1030667E (pt) | 2005-06-30 |
| WO1999025356A1 (en) | 1999-05-27 |
| NO20002218L (no) | 2000-05-12 |
| PL340467A1 (en) | 2001-02-12 |
| AU1754899A (en) | 1999-06-07 |
| IL135825A0 (en) | 2001-05-20 |
| DE69829202T2 (de) | 2005-07-21 |
| US6303595B1 (en) | 2001-10-16 |
| NO20002218D0 (no) | 2000-04-28 |
| BR9815098A (pt) | 2000-10-10 |
| HK1029932A1 (en) | 2001-04-20 |
| JP2001522891A (ja) | 2001-11-20 |
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